Using primary culture of cerebellar granule cells, we have previously found that these cells possess alpha 1-adrengeric, histaminergic H1. 5-HT4 and muscarinic cholinergic receptors coupled to phospholipase C. Prestimulation with each of these receptors agonists was found to cause a time-dependent desensitization to subsequent stimulation with the desensitizing agonist. In all cases, the responses mediated by receptors which were not prestimulated remained virtually uncharged, thus indicating homologous desensitization. Biologically active phorbol esters rapidly desensitizes the responses mediated by carbachol, histamine, norepinephrine and serotonin, suggesting that activation and translocation of protein kinase C may play a role in the desensitization of phospholipase C-coupled receptors. Granule cells also express GABA A and GABA B receptors. We found that 7- day exposure of these cells to 50 muM GABA significantly increased the efficacies of carbachol and excitatory amino acids such as quisqualate. L-glutamate, N-methyl-D-aspartate in inducing phosphoinositide (PI) hydrolysis by phospholipase C. This increase was associated with enhancement of the maximal extent of stimulation without significantly affecting the EC50 of these agents. No significant changes in the efficacies and EC50 of norepinephrine and kainate were found after GABA pretreatment. These changes in PI response mediated by muscarinic cholinergic and glutamatergic receptors may underlie some pharmacological effects elicited by long-term treatment with benzodiazepines and barbiturates. In addition, we found that stimulation of GABA B receptors in granule cells results in inhibition of voltage sensitive calcium uptake and concomitant inhibition of the release of preloaded D-aspartate from granule cells. Thus, cerebellar granule cells express multiple types of cell-surface receptors coupled to various effector systems and is an excellent model for studying the regulation of neurotransmitter receptors.